The Chemical Regulatory Landscape of Biomolecular Condensates

ABSTRACT

Biomolecular condensates, formed via liquid–liquid phase separation (LLPS), play crucial roles in a range of cellular processes. Dysregulated or aberrant condensates are closely associated with diseases including neurodegeneration, cancer, metabolic disorders, and viral infections. Accumulating evidence demonstrates that LLPS is highly amenable to chemical regulation. Diverse chemical agents can modulate phase separation by directly or indirectly perturbing the weak, multivalent interactions that govern condensate formation, dissolution, size, material properties, and maturation. The identification of LLPS‐modulating chemical regulators not only provides powerful probes for dissecting the physicochemical principles underlying condensate behavior, but also highlights emerging opportunities for the development of condensate‐targeting strategies of potential therapeutic relevance. In this review, we summarize recent advances in the chemical regulation of LLPS, organizing regulatory strategies according to their dominant mechanistic level of action. We highlight how chemical perturbations reshape phase behavior by altering conformational ensembles, effective interaction valency, electrostatic and metabolic environments, or bulk solvent properties, thereby shifting phase boundaries or biasing pathological liquid‐to‐solid transitions. Finally, we discuss emerging opportunities and remaining challenges in the rational discovery of selective, mechanism‐informed LLPS regulators.